FI120394B - Substituted benzene sulfonylureas and thioureas, process for their preparation and use in the manufacture of pharmaceutical preparations and those containing pharmaceutical preparations - Google Patents

Description

Substituted benzenesulfonyl ureas and thioureas, their process and their use in the preparation of pharmaceutical preparations, and pharmaceutical preparations containing them

The invention relates to substituted benzenesulfonylureas and thioureas of formula I

, IIKr ^ 'WYK' '((i) ^ * / (,>' <*>) wherein: 10 R (1) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, or cycloalkyl having 3, 4, 5 or 6 C atoms; R (2} is a C 1-6 chain in which 1 to 3 C atoms may be replaced by a heteroatom O, NH or S, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, mercaptoalkyl having 1, 2, 3, 4, 5 or 6 carbon atoms. A C atom, or a cycloalkyl having 3, 4, 5 or 6 C atoms-IHXC1; R (3) and R (4) (the same or different) represent hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 C atoms or together form a chain (012) 2-5; E is oxygen or sulfur; X is oxygen or sulfur; Y is a hydrocarbon chain of formula [CR (5) 2] m wherein R (5) is hydrogen or alkyl having 1 or 2 carbon atoms; and m is 1 or 2;

Ar is a phenyl, thienyl, furyl, pyrrolyl, thiazolyl, naphthyl or pyridyl group which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of alkyl having 1 or 2 C atoms, alkoxy having 1 or 2 C atoms, Cl, Br and F.

2 The term alkyl, unless otherwise indicated, means saturated or unbranched saturated hydrocarbon groups. The cycloalkyl group may additionally have an alkyl substituent. Useful halogen substituents include fluorine, chlorine, bromine and iodine. Further, the compounds may exist with chiral centers, optionally in the alkyl chains Y, R (2), R (3) and R (4). In this case, the invention encompasses both individual antipodes as such and in a mixture of both enantiomers in different ratios, and includes meso compounds or mixtures of meso compounds, enantiomers, or diastereomers.

Similar sulfonylureas with blood glucose lowering activity are known from BE 754 454.

15 Compounds I are active pharmaceutical ingredients in human and veterinary medicine. In addition, they can be used as intermediates in the manufacture of other active pharmaceutical ingredients.

Preferred are compounds I wherein: R (1) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, or cycloalkyl having 3, 4, 5 or 6 carbon atoms; R (2) is alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, mercaptoalkyl having 1, 2 , 3, 4, 5 or 6 C atoms, 25 cycloalkyl having 3, 4, 5 or 6 C atoms, or a C 1-6 chain in which 1 to 3 C atoms may be replaced by heteroatom O 1, NH or S; R (3) and R (4) (the same or different) represent hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, or together form a chain (CH 2 is sulfur; X is oxygen; Y is a hydrocarbon chain of formula [CR (5) 2] i-2, R (5) is hydrogen or alkyl having 1 or 2 carbon atoms; 35 Ar is phenyl, thienyl , a furyl, pyrrolyl, thiazolyl, naphthyl or pyridyl group which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of alkyl having 1 or 2 carbon atoms, alkoxy having 1 or 2 C atoms, Cl, Br and F.

Particularly preferred are compounds I wherein: R (1) is hydrogen or alkyl having 1 or 2 carbon atoms; R (2) is alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms; R (3) and R (4) (the same or different) represent hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; E is sulfur; X is oxygen; Y is a hydrocarbon chain of formula (CH 2) i-2, *

Ar is a phenyl, thienyl, furyl, pyrrolyl, thiazolyl, naphthyl or pyridyl group which is unsubstituted or substituted with 1-3 substituents selected from alkyl having 1 or 2 C atoms, alkoxy having 1 or 2 C atoms, Cl, Br and F.

A further preferred group is compounds I, wherein: R (1) is hydrogen or alkyl having 1 or 2 carbon atoms; R (2) is alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms; R (3) and R (4) (the same or different) are hydrogen or methyl; E is sulfur; X is oxygen; Y is the hydrocarbons ju of the formula (0¾) 1-2; Ar is a thienyl, furyl, pyrrolyl, thiazolyl, naphthyl or pyridyl group which is unsubstituted or substituted with 1-3 substituents selected from alkyl having 1 or 2 carbon atoms, alkoxy having 1 or 2 C atoms, Cl, Br and F.

Also preferred are compounds of formula I wherein: 4 R (1) is hydrogen or alkyl having 1 or 2 carbon atoms; R (2) is alkoxy having 1, 2, 2, 4, 5 or 6 carbon atoms; R (3) and R (4) (the same or different) are hydrogen or methyl; E is sulfur; X is oxygen; Y is a hydrocarbon chain of formula (CH 2) i-2; Ar is phenyl which is unsubstituted or substituted with 1-3 substituents selected from the group consisting of alkyl having 1 or 2 carbon atoms, alkoxy having 1 or 2 carbon atoms, Cl, Br and F.

The compounds of this invention are valuable drugs for the treatment of cardiac arrhythmias of various origins and for the prevention of sudden cardiac deaths due to arrhythmias, and therefore may have utility as anti-arrhythmic agents. Examples of arrhythmic cardiac arrhythmias are supraventricular-20 laryngeal arrhythmias such as atrial tachycardia, atrial fibrillation or seizure-related supraventricular arrhythmias, or ventricular arrhythmias such as ventricular arrhythmias, particularly life-threatening ventricular tachycardias. They are particularly suited to cases in which arrhythmias result from coronary artery stenosis, such as those occurring in angina pectoris or during a sudden myocardial infarction or as a chronic consequence of a myocardial infarction. They are therefore particularly suitable for the prevention of sudden cardiac death in patients with myocardial infarction. Other diseases in which such arrhythmias and / or sudden cardiac death due to arrhythmias play a role include, for example, cardiac failure or cardiac hypertrophy due to chronically elevated blood pressure.

In addition, the compounds may have a positive effect on the reduced cardiac contractility. This may be a case of impaired cardiac contractility, such as in the case of cardiac insufficiency, but also acute cases, such as cardiac injury in shock. Similarly, in cardiac transplantation, the heart may regain its functional capacity faster and more securely after surgery. The same goes for cardiac surgery, where cardiac surgery must be temporarily stopped with cardioplegic solutions.

The invention further relates to a process for the preparation of compounds I10, characterized in that (a) aromatic sulfonamides of the formula IIo. 0 u R (2) ^ X Rh) '<*>

I I

or salts thereof of formula III

R (2) R (3) (]

f j I

15 is reacted with R (1) substituted isocyanates of formula IV

R (1) -N = C = O 20 for substituted benzenesulfonyl ureas Ia (E = oxygen) "'' '/ τή'ΐΥ' x r {3) R <4>

The cations M in the salts of the formula III include alkali, earth alkaline, ammonium and tetraalkylammonium ions. Similarly, R (1) substituted isocyanates IV can be used R (1) substituted carbamic acid esters, R (1) substituted carbamic acid halides or R (1) substituted ureas.

5 (b) Unsubstituted Benzenesulfonylureas Ia [R (1) -H, E-O] may be prepared by reaction of aromatic benzenesulfonamide of formula II or its salt III with trialkylsilyl isocyanate or silicon tetraisocyanate and cleavage (e.g. by hydrolysis). silicon substituted benzenesulfonylureas.

Further, it is possible to convert benzenesulfonamide II or a salt thereof III by reaction with halogenocyanes and hydrolysis of primary N-cyanosulfonamides formed with mineral acids at temperatures of 0 ° C to 100 ° C to benzenesulfonyl urea 1a.

(c) Benzenesulfonyl urea Ia (where E = oxygen) may be prepared from aromatic benzenesulfonamide II or a salt thereof with R 1 (1) substituted trichloroacetamide of formula V

/ NHR (1)

CI3C-

In the presence of 0 20 bases in an inert solvent according to Synthesis 1987, 734-735 at temperatures between 25 ° C and 150 ° C.

Suitable bases are, for example, alkali metal or alkaline earth metal hydroxides, hydrides, amides or also alcoholates such as sodium hydroxide, potassium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydride, sodium potassium, potassium ethanal, potassium ethanal, potassium ethanal, Suitable inert solvents include ethers such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether (di-glyme), ketones such as acetone or butanone, nitriles such as acetonitrile, nitro compounds such as nitromethane, 7-esters such as ethyl acetate, amide, DMF) or N-methylpyrrolidone (NMP), phosphoric acid-hexamethyl triamide, sulfoxides such as DMSO, sulfones such as sulfolane, hydrocarbons such as benzene, toluene, 5 xylene. Mixtures of these solvents with each other are also suitable.

(d) Benzenesulfonylthiourea Ib (E = S), (,) ^ VrrYK, r 1 - ((2) ^ X R (3) R (4)

Prepared from benzenesulfonamide II or a salt thereof 10 III and R (1) -substituted isothiocyanate VI

R (1) -N = C = S

The unsubstituted benzenesulfonylthiourea Ib [R (1) = H, 15 X = S] can be prepared by the reaction of aromatic benzenesulfonamide II or its salt III with trimethylsilyl isothiocyanate or silicon tetraisothiocyanate and primary silicon-substituted benzenesulfonylurea (hydrolyzate). Further, it is possible to react the aromatic benzenesulfonamide II or its salt III with benzoyl isothiocyanate and to react the benzoyl substituted intermediate benzenesulfonylthiourea with aqueous mineral acid to form Ib [R (1) = H, E = S]. Similar methods are described in J. Med. Chem. 1992, 35, 1137-1144. Another alternative is to react the N-cyanosulfonamides mentioned in Method 1 with hydrogen sulfide.

e) The substituted Bent-30 benzenesulfonylurea of formula Ia (E = oxygen) can be prepared by the conversion reaction of benzenesulfonylthiourea of structure Ib (E = S). Substitution of the sulfur atom with an oxygen atom in the correspondingly substituted benzenesulfonylthiourea can be effected, for example, by heavy metal oxides or salts or also by the use of oxidizing agents such as hydrogen peroxide, sodium peroxide or nitric acid. Thiourea can also be desulfurized by treatment with phosgene or phosphorus pentachloride. Intermediate compounds provide chloroformic acid amidines or carbodiimides, respectively, which are converted to the corresponding substituted benzenesulfonylureas by, for example, saponification or addition of water. Isothioureas behave as sulfur removers as thioureas and thus act as starting materials for these reactions.

(f) Benzenesulfonylurea Ia can be prepared from benzenesulfonyl halide of formula VII

VM

R (2) - (X) (k) * <*> 15 R (1) -substituted urea or R (1) -substituted bis (tri-alkylsilyl) urea. Further, sulfonic acid chloride VII can be reacted with parabic acids to form benzenesulfonylparabanic acid, which by hydrolysis with mineral acids yields the corresponding benzenesulfonylurea 1a.

(g) Benzenesulfonylurea 1a can be prepared by reaction of an amine of formula R (1) -NH 2 with benzenesulfonyl isocyanates of formula VIII

° -c-N> rrvK4r v, n R <2) ^ *. {S) R (4> 25

Similarly, the amine R (1) -NH 2 can be reacted with the benzenesulfonylurea acid ester, the carboxylic acid halide or benzenesulfonylurea Ia [wherein R (1) = H] to form Ia.

9

(h) Benzenesulfonylthiourea Ib may be prepared by reaction of a crude amine of formula R (1) -NH 2 with benzenesulfonyl isothiocyanates of formula IX

\ // ° H

Similarly, the amine R (1) -NH 2 can be reacted with benzenesulfonylcarbamic acid thioester or urea acid potassium halide to form Ib.

The sulfonyl isothiocyanate was prepared by reaction of the corresponding sulfonic acid amide with an equimolar amount of alkali metal hydroxide and sulfur carbon in an organic solvent such as DMF, DMSO, N-methylpyrrolidone. The dialkyl metal salt of the sulfonyl dithiocarbamic acid thus obtained is reacted in an inert solvent with a slight excess of phosgene or the like, such as triphosgene, chloroformic acid ester (2 equivalents) or thionyl chloride. The solution of the sulfonyl isothiocyanate thus obtained can be reacted directly with the corresponding amines or ammonia.

(i) The correspondingly substituted benzenesulfenyl 20 or sulfinyl urea can be oxidized with an oxidizing agent such as hydrogen peroxide, sodium peroxide or nitric acid to the benzenesulfonyl urea Ia.

Compounds I and their physiologically acceptable salts are valuable therapeutic agents which are useful not only as anti-arrhythmic agents but also as a prophylactic in cardiovascular disorders, cardiac failure, cardiac transplantation or cerebrovascular disease in humans (e.g. 30 in guinea pigs and cats). Physiologically acceptable salts of compounds I, as used in Remmington's Pharmaceutical Science, 17th edition, 1985, pages 14-18, means compounds of formula XII

10 "'' Y ^ wyv; ' R (2) ^^ * * (5) R <4> and may be prepared from non-toxic organic and inorganic bases and substituted benzenesulfonylureas I. Salts wherein M in formula XII may be sodium, potassium, , rubidium, calcium, magnesium, ammonium ions, and acid addition products of basic amino acids such as lysine or arginine.

The starting compounds for said methods for the synthesis of benzenesulfonyl-10 urea I are prepared according to methods known per se (e.g., in manuals such as Houben-Weyl, Methode der Organischen Chemie, Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc.). and in the patent applications set forth above), under reaction conditions known to and suitable for said reactions. In this case, alternatives known per se but not specifically mentioned may be used. If desired, the starting materials may also be formed in situ so that they are not isolated from the reaction mixture, but are immediately reacted further.

Then, for appropriately substituted carboxylic acids of formula XIII 11 I i

Halogen sulfonation followed by sulfonamide XIV obtained by ammonolysis can be performed

11 '^ OT "R (2)

XIV

may be reacted with the corresponding amine R (3) R (4) NH, when the carboxylic acid group is activated, to form the carboxyl-5-fatty acid amide of formula II

V ° Y 5 / * r • / WYK, X R (3) R (<)

! I

Activation methods include the preparation of carboxylic acid chloride or ester or carboxylic acid mixed anhydrides with formic acid halides. In addition, known reagents for amide bond formation such as carbonyl bisimidazole, dicyclohexylcarbodiimide and propane phosphoric acid anhydride may be used.

The sulfonamides XIV are prepared by known methods and reaction conditions known for and suitable for said reactions. In this case, well-known but not specifically mentioned alternatives may also be used. If desired, the syntheses may be carried out in one, two or more steps. Particularly preferred are processes for converting acid XIII to aromatic at temperatures of -10 ° C to 120 ° C, preferably 0 ° C to 100 ° C, in the presence or absence of inert solvents with electrophilic reagents. sulfonic acids and their derivatives such as sulfonic acid halides. Sulfonations can be carried out, for example, with sulfuric acids or fuming sulfuric acids, halogen sulfonations with halosulfonic acids, reactions with sulfuryl halides in the presence of anhydrous metal halides, or thionyl halides in the presence of anhydrous metal halides and the following known acid halides. If the sulfonic acids are the primary reaction products, they can be modified either directly or by treatment with tertiary amines such as pyridine or trialkylamines, or alkali or alkaline earth metal hydroxides or reagents forming this basic compound in situ, in known manner such as acid halides such as phosphorus trihalides, phosphorus pentahalides, phosphorus oxychlorides, thionyl halides, oxalyl halides to sulfonic acid halides. Conversion of sulfonic acid derivatives to sulfonamides is carried out in a manner known in the literature, preferably the sulfonic acid chlorides are reacted in inert solvents at 0 ° C to -1500 ° C with aqueous ammonia in acetone or THP. Further, the aromatic sulfonamides XIV can be synthesized according to methods described in the literature from acids XIII or their esters by reaction with organic alkali or alkaline earth metals in inert solvents and in an inert gas atmosphere at -100 ° C to 50 ° C, preferably -100 ° C. 30 ° C, at temperatures using sulfur dioxide followed by heat treatment with an NH 2 donor such as amidosulfonic acid.

The compounds I according to the invention and their physiologically acceptable salts can be used in the preparation of pharmaceutical preparations, in particular in a non-chemical manner. They may then be formulated in a suitable dosage form with at least one solid or liquid carrier or excipient alone or in combination with other cardiovascular active drugs such as calcium antagonists, NO donors or ACE inhibitors. These preparations can be used as medicaments in human or veterinary medicine. Suitable carriers include organic or inorganic substances suitable for enteral (e.g., oral), parenteral (e.g., intravenous), or topical (13) applications, and do not react with novel compounds, e.g., water, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol gelatins, carbohydrates such as lactose or starch, magnesium stearate, talc, lanolin, petrolatum. Particularly suitable for oral use are tablets, granules, capsules, syrups, juices or drops, solutions for rectal administration, preferably oily or aqueous solutions, and suspensions, emulsions or implants, topical ointments, creams, pastes, lotions, gels, sprays. , foams, aerosols, solutions (e.g., in alcohols such as ethanol or isopropanol, acetonitrile, DMF, dimethylacetamide, 1,2-propanediol or mixtures thereof with one another or with water) or powders. The novel compounds 15 may also be lyophilized and the resulting lyophilisates used, for example, for the preparation of injection preparations. Particularly for topical use, liposome preparations are also contemplated. Containing stabilizing and / or wetting agents, emulsifying agents, salts and / or auxiliaries, such as lubricating, preserving, stabilizing and / or wetting agents, emulsifying agents, salts which act on the osmotic pressure, buffering agents, coloring agents. and flavoring and / or flavoring agents. If desired, they may also contain one or more other active ingredients, for example one or more vitamins.

The dosages required for the treatment of cardiac arrhythmias with Compounds I depend on whether the treatment is acute or prophylactic. Generally, the dosage range will be at least about 0.1 mg, preferably at least 1 30 mg, up to 100 mg, preferably up to 10 mg, per kilogram per day for prophylaxis. The dose may then be divided into a single oral or parenteral dose or up to four single doses. When treating acute cases of cardiac arrhythmias, for example in intensive care, parenteral administration may be preferred. The preferred dosage range for critical situations can then be 10-100 mg and administration can be by, for example, continuous intravenous infusion.

According to the invention, in addition to the compounds described in the applicable examples, the compounds I which are summarized in the following table can be obtained: 1} W-5- (1-phenylethyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N1-methylthiourea 2) N-5- { 1- (2-furyl) ethyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylthiourea 3) N-5- (1- (3-furyl) ethyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N1 -methylthiourea 4) N-5- (1- (2-thienyl) ethyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N1-methylthiourea 15 5) n-5- (1- (3-thienyl) ethyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylthiourea 6) N-5- (1- {2-pyrrolyl} ethyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N1-methylthiourea 7} N-5- (1- (3-Pyrrolyl) ethyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylthiourea 8) N-5- (1- (2-thiazolyl) ethyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N1-methylthiourea 9) N-5 - {1- (3-thiazolyl) ethyl) aminokarbo Nylmethyl-2-methoxyphenylsulfonyl-N1-methylthiourea 25) N-5- (1- (2-furyl) ethyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylurea 11) N-5- (1- (3-furyl) ethyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylurea 12) N-5- (1- (2-thienyl) ethyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylurea 13) N-5- (1- (3-thienyl) ethyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylurea 14) N-5- (1- (2-pyrrolyl) ethyl) aminocarbonylmethyl-2-methoxyphenyl sulfonyl-N'-methylurea 35 (15) N-5- (1- (3-pyrrolyl) ethyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-Ν'-methyl urea 15 16) N-5- (1- (2-thiazolyl) ethyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylurea 17) N-5- (1- (2-furyl) ethyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N1-methylthiourea 5 18) N-5 ~ ( 1- (3-furyl) ethyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N'-methylthiourea 19) N-5- (1- (2-thienyl) ethyl) aminocarb onylmethyl 2-methylphenylsulfonyl-N'-methylthiourea 20) N-5- (1- (3-thienyl) ethyl) aminocarbonylmethyl-2-methyl-phenylsulfonyl-N'-methylthiourea 21) N-5- (1- (2-Pyrrolyl) ethyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N'-methylthiourea 22) N-5- (1- (3-Pyrrolyl) ethyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N'-methylthiourea 15 23) N -5- (1- (2-Thiazolyl) ethyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N'-methylthiourea 24) N-5- (1- (3-Thiazolyl) ethyl) aminocarbonylmethyl-2-methylphenylsulfonyl- N'-methylthiourea 25) N-5- (1- (2-furyl} ethyl) aminocarbonylmethyl-2-methyl-20-phenylsulfonyl-N'-methylurea 26} N-5- (1- (3-furyl) ethyl) aminocarbonylmethyl -2-methylphenylsulfonyl-N1-methylurea 27) N-5- (1- (2-thienyl) ethyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N1-methylurea 28) N-5- (1- ( 3-thienyl) ethyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N1-methylurea 29) N-5- (1- (2-pyrrolyl) ethyl) over) aminocarbonylmethyl-2-methylphenylsulfonyl-N'-methylurea 30) N-5- (1- (3-pyrrolyl} ethyl) aminocarbonylmethyl-2-30 methylphenylsulfonyl-N'-methylurea 31) N-5- (1- (2-Thiazolyl) ethyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N'-methylurea 32) N-5- (1- (3-Thiazolyl) ethyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N'-methylurea 35 33) N- 5- (1- (2-furyl) ethyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N'-methylthiourea 16 34) N-5- (1- (3-furyl) ethyl) aminocarbonylmethyl-2- methyl thiophenylsulfonyl-N'-methylthiourea 35) N-5- (1- (2-thienyl) ethyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N1-methylthiourea 5 36) N-5- (1- (3-thienyl) ethyl) ) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N1-methylthiourea 37) N-5- (1- (2-pyrrolyl) ethyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N1-methylthiourea 38} N-5- (1- (3-pyrrolyl) ) ethyl) aminocarbonylmethyl-2-10 methylthiophenylsulfonyl-N'-methylthi ourea 39) N-5- (1- (2-Thiazolyl) ethyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-Ν'-methylthiourea 40) N-5- (1- (3-Thiazolyl) ethyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N '-methylthiourea 15 41) N-5- (1- (2-furyl) ethyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N 1 -methylurea 42) N-5- {1- (3-furyl) ethyl) aminocarbonylmethyl-2 -methylthiophenylsulfonyl-N '-methyl urea 43) N-5- (1- (2-thienyl) ethyl} aminocarbonylmethyl-2-methyl-20-thiophenylsulfonyl-4'-methylurea 44} N-5- (1- (3-thienyl}) ethyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N1-methylurea 45) n-5- (1- (2-pyrrolyl) ethyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N'-methylurea 25 46) N-5- (1- ( 3-Pyrrolyl) ethyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N'-methylurea 47) N-5- (1- (2-thiazolyl) ethyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N'-methylurea 48) N-5- (1 - (2-furyl) ethyl) aminocarbonylmethyl-2-ethoxy-30-siphenylsulfo Nyl-N'-methylthiourea 49) N-5- (1- (3-furyl) ethyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N1-methylthiourea 50) N-5- (1- (2-Thienyl) ethyl) aminocarbonylmethyl -2-ethoxyphenylsulfonyl-N'-methylthiourea 35 51) n-5- (1- (3-thienyl) ethyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N 1 -methylthiourea 17 52) N -5- (1- (2-Pyrrolyl) ethyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N'-methylthioea 53) N-5- (1- (3-pyrrolyl) ethyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl -N 1 -methylthiourea 5 54) N-5- (1- (2-thiazolyl) ethyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N 1 -methylthiourea 55) N-5- {1- (3-thiazolyl) ethyl) aminocarbonylmethyl-2- ethoxyphenylsulfonyl-N'-methylthiourea 56) N-5- (1- (2-furyl) ethyl) aminocarbonylmethyl-2-ethox-10-biphenylsulfonyl-N'-methylurea 57) N-5- (1- (3-furyl) ethyl) ) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N'-methylurea 58) N-5- (1- (2-thienyl) ethyl) aminocarbonylmethyl-2-ethoxyphen ylsulfonyl-N'-methylurea 15 59) N-5- (1- (3-thienyl) ethyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N'-methylurea 60) N-5- (1- (2-pyrrolyl) ethyl) aminocarbonylmethyl -2-ethoxyphenylsulfonyl-N'-methylurea 61) N-5- (1- (3-pyrrolyl) ethyl) aminocarbonylmethyl-2-20-ethoxyphenylsulfonyl-N'-methylurea 62) N-5- (1- (2-thiazolyl) ethyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N1-methylurea 63} N-5- (1- (2-furyl) ethyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N'-methylthiourea 25 64) n-5- (1- ~ 3-furyl) ethyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N1-methylthiourea 65) N-5- (1- (2-thienyl) ethyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N'-methylthiourea 66) N-5 - (1- (3-Thienyl) ethyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N'-methylthiourea 67) N-5- (1- (2-pyrrolyl) ethyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N'-methylthiourea 68) N-5- (1- (3-Pyrrolyl) ethyl) aminocarbonylmethyl-2-propoxyphenyl isulfonyl-N'-methylthiourea 35 69) N-5- (1- (2-thiazolyl) ethyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N'-methyl thiourea 18 70) N-5- (1- (3- thiazolyl) ethyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N'-methylthiourea 71) N-5- (1- (2-furyl) ethyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N1-methylurea 5 72) N -5- (1- (3-furyl) ethyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N'-methylurea 73) N-5- (1- (2-thienyl) ethyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N 1 -methylurea 74) N-5- (1- (3-thienyl) ethyl) aminocarbonylmethyl-2-pro-10 -oxyphenylsulfonyl-N'-methylurea 75) N-5- (1- (2-pyrrolyl) ethyl) aminocarbonylmethyl-2 -propoxyphenylsulfonyl-N1-methylurea 76) N-5- (1- (3-pyrrolyl) ethyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N'-methylurea 15 77} N-5- (1- (2-thiazolyl) ethyl) aminocarbonylmethyl -2-Propoxyphenylsulfonyl-N1-methylurea 78) N-5- (1-phenylpropyl) aminocarbonylmethyl-2-prop oxyphenylsulfonyl-N'-methylthiourea 79) N-5- (1- (2-furyl) propyl) aminocarbonylmethyl-2-20 methoxyphenylsulfonyl-N'-methylthiourea 80) N-5- (1- (3-furyl) propyl ) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylthiourea 81) N-5- (1- (2-thienyl) propyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylthiourea 25 82) N-5- (1- ( 3-Thienyl) propyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N1-methylthio 83) N-5- (1- (2-pyrrolyl) propyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N1-methylthio our 84) N -5- (1- (3-Pyrrolyl) propyl) aminocarbonylmethyl-2 -30 methoxyphenylsulfonyl-N'-methylthiourea 85) N-5- (1- (2-thiazolyl) propyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N '-methylthiourea 86) N-5- (1- (3-thiazolyl) propyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylthiourea 35 87) N-5- (1- (2- furyl) propyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N1-methylurea 19 88) N-5- (1- { (3-furyl) propyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylurea (89) N-5- (1- (2-thienyl) propyl} aminocarbonylmethyl-2-methoxyphenylsulfonyl-N1-methylurea 5 90) N-5- (1- (3-thienyl) propyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylurea 91) N-5- (1- (2-pyrrolyl) propyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N 92-N-5- (1- (3-Pyrrolyl) propyl) aminocarbonylmethyl-2-10 methoxyphenylsulfonyl-N1-methylurea 93} N-5- (1- (2-Thiazolyl) propyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl -N 1 -methyl urea 94} N-5- (1- (2-furyl) propyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N 1 -methylthiourea 15 95) N-5- (1- (3-furyl) propyl) aminocarbonylmethyl- 2-methylphenylsulfonyl-N 1 -methylthiourea 96) N-5- (1- (2-thienyl) propyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N 1 -methylthiourea 97) n-5- (1- (3 -thienyl) propyl) aminocarbonylmethyl-2-20 methylphenylsulfonyl-N1-methylthi 98) N-5- (1- (2-pyrrolyl) propyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N1-methylthiourea 99) N-5- {1- (3-pyrrolyl) propyl) aminocarbonylmethyl -2-methylphenylsulfonyl-N1-methylthiourea (100) N-5- (1- (2-thiazolyl) propyl) aminocarbonylmethyl-2-methylbenzylsulfonyl-N1-methylthiourea (101) N-5- (1- (3-thiazolyl) propyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N1-methylthiourea 102) N-5- (1- (2-furyl) propyl) aminocarbonylmethyl-2-30 methylphenylsulfonyl-N1-methylurea 103) N-5- (1- (3-furyl) propyl) ) aminocarbonylmethyl-2-methylphenylsulfonyl-N1-methylurea 104) N-5- (1- (2-thienyl) propyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N1-methylurea 35105) N-5- (1- (3-thienyl) propyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N 1 -methyl urea 20 106) N-5- (1- (2-pyrrolyl} propyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N'-methyl urea 107) n-5- (1- (3 -pyrrolyl) propyl) aminocarbonylmethyl-2-methyl fe Nylsulfonyl-N1-methylurea 5108) N-5- (1- (2-thiazolyl) propyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N'-methylurea 109) N-5- (1- (3-Thiazolyl) propyl ) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N1-methylurea 110) N-5- (1- (2-furyl) propyl) aminocarbonylmethyl-2-10-methylthiophenylsulfonyl-N'-methylthiourea 111) N-5- (1- (3-furyl) ) propyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N1-methylthiourea 112} N-5- (1- (2-thienyl) propyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N1-methylthiourea 15 113) N-5- (1- (3- thienyl) propyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N1-methylthiourea 114) N-5- (1- (2-pyrrolyl) propyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N'-methylthiourea 115) N-5- ( 1- (3-Pyrrolyl) propyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N'-methylthiourea 116) N-5- (1- (2-Thiazolyl) propyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N'-methylthio o urea 117) N-5- (1- (3-thiazolyl) propyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N'-methylthioea 118) N-5- (1- (2-furyl) propyl) aminocarbonylmethyl - 2-methylthiophenylsulfonyl-N'-methylurea 119) N-5- (1- (3-furyl) propyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N'-methylurea 120) N-5- (1- (2-Thienyl) propyl) aminocarbonylmethyl-2-30 methylthiophenylsulfonyl-N'-methyl urea 121) N-5- (1- (3-Thienyl) propyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N'-methylurea 122) N-5- (1- (2-Pyrrolyl) propyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N'-methyl urea 35 123) N-5- (1- (3-Pyrrolyl) propyl) aminocarbonylmethyl-2-methylthio-phenylsulfonyl-N'- methyl urea 21,124) N-5- (1- (2-thiazolyl) propyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N'-methyl urea 125) N-5- (1- (2-furyl) propyl) aminocarbonylmethyl-2-ethoxy enyl sulfonyl-N'-methylthiourea 5,126) N-5- (1- (3-furyl) propyl) amide nocarbonylmethyl-2-ethoxyphenylsulfonyl-N'-methylthiourea 127) N-5- (1- (2-thienyl) propyl) aminocarbonylmethyl-2-ethoxenylsulfonyl-N'-methylthiourea 128) N-5- (1- (3-Thienyl) propyl) aminocarbonylmethyl-2-10 ethoxyphenylsulfonyl-N'-methylthiourea 129) N-5- (1- (2-pyrrolyl) propyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N'-methylthiourea 130) N-5- (1- (3-Pyrrolyl) propyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N'-methylthiourea 151) N-5- (1- (2-thiazolyl) propyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N'-methylthiourea 132) N -5- (1- (3-Thiazolyl) propyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N'-methylthiourea 133) N-5- (1- (2-furyl) propyl) aminocarbonylmethyl-2-20 ethoxyphenylsulfonyl-N'-methylurea 134) N-5- (1- (3-furyl) propyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N'-methylurea 135) N-5- (1- (2-thienyl) propyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl -N'-methyl urea 25 136) N-5- (1- (3-thienyl) propyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N'-methylurea 137) N-5- (1- (2-pyrrolyl) propyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N1-methylurea 138 ) N-5- {1- (3-pyrrolyl) propyl) aminocarbonylmethyl-30-ethoxyphenylsulfonyl-N'-methylurea 139) N-5- (1- (2-thiazolyl) propyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N ' -methylurea 140) N-5- (1- (2-furyl) propyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N'-methylthiomethane 35 141) n-5- (1- (3-furyl) propyl) aminocarbonylmethyl- 2-propoxy phenylsulfonyl-N'-methylthiourea 22 142) N-5- (1- (2-thienyl) propyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N'-methylthiourea 143) N-5- {1- { 3-Thienyl) propyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N 1 -methylthiourea 144 144) N-5- (1- (2-pyrrolyl) propyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N'-methylthiourea 145 ) N-5- (1- (3-pyrrolyl) propyl) aminocarbonylmethyl-2-prop oxy enylsulfonyl-N'-methylthiourea 146) N-5- (1- (2-thiazolyl) propyl) aminocarbonylmethyl-10-propoxyphenylsulfonyl-N'-methylthiourea 147) N-5- (1- (3-thiazolyl) propyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N'-methylthiourea 148) N-5- (1- (2-furyl) propyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N1-methylurea 15 149) N-5- ( 1- (3-furyl) propyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N1-methylurea 150) N-5- (1- (2-thienyl} propyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N'-methylurea 151) N-5- (1- (3-thienyl} propyl) aminocarbonylmethyl-2-20 propoxyphenylsulfonyl-N'-methylurea 152) N-5- (1- (2-pyrrolyl) propyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N 1 (methyl urea 153) n-5- (1- (3-pyrrolyl) propyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N'-methylurea 25154) N-5- (1- (2-thiazolyl) propyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl -N'-methylurea 155) N-5- (1-phenyl) N-5- (1- (2-furyl) -1-methylethyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N1-methylthiourea 156) N-5-Methylethyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N'-methylthiourea 156) N-5 - (1- (3-Furyl) -1-methylethyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylthiourea 158) N-5- (1- (2-thienyl) -1-methylethyl) aminocarbonylmethyl -2-methoxyphenylsulfonyl-N'-methylthiourea 35,159) N-5- (1- (3-thienyl) -1-methylethyl) aminocarbonylmethyl-1-2-methoxyphenylsulfonyl-N1-methylthiourea 23 160) N-5- (1- (2-Pyrrolyl) -1-methylethyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N1-methyl ourea 161) N-5- (1- (3 (Pyrrolyl) -1-methylethyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylthiourea 5 162) N-5- (1- (2-thiazolyl) -1-methylethyl) aminocarbonyl-1-methyl- 2-methoxyphenylsulfonyl-N'-methylthiourea 163) N-5- (1- (3-thiazolyl) -1-methylethyl) aminocarbonylmethyl-2-methoxyphenyl sulfonyl-N'-methylthiourea 164) N-5- (1- (2-furyl) -1-methylethyl) aminocarbonyl-10-methyl-2-methoxyphenylsulfonyl-N'-methylurea 165) N-5- (1- (3 -furyl) -1-methylethyl} aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylurea 166) N-5- (1- (2-thienyl) -1-methylethyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl -N '-methyl urea 15 167) N-5- (1- (3-thienyl) -1-methylethyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methyl urea 168) N-5- ( 1- (2-pyrrolyl) -1-methylethyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylurea 169) N-5- (1- (3-pyrrolyl) -1-methylethyl) aminocarbonyl-20-methyl-2- methoxyphenylsulfonyl-N1-methylurea 170) N-5- (1- (2-thiazolyl) -1-methylethyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylurea 171) N-5- (1- (2-furyl) -1-methylethyl) aminocarbonylmethyl-2-methylenenylsulfonyl-N1-methylthiourea 25,172) N-5- (1- (3-furyl) -1-methylethyl) aminocarbonylmethyl-2-methylphenyl 173) N-5- (1- (2-thienyl) -1-methylethyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N1-methylthio 174) N-5- (1- (3-Thienyl) -1-methylethyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N1-methylthiourea 175) N-5- (1- (2-pyrrolyl) -1-methylethyl) aminocarbonylmethyl-2-methylphenyl sulfonyl-N 1 -methyl-thiourea 176} N-5- (1- (3-pyrrolyl) -1-methylethyl) aminocarbonylmethyl-2-methyl-phenylsulfonyl-N- [methyl-thiourea 35,177) N-5- (1- (2-Thiazolyl) -1-methylethyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N'-methylthiourea 24,178) N-5- (1- (3-Thiazolyl) -1-methylethyl} aminocarbonyl-1-methyl-2 -methyl phenyl sulfonyl-N1-methylthiourea 179) N-5- (1- (2-furyl) -1-methylethyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N1-methylurea 5 180) N- 5- (1- (3-Furyl) -1-methylethyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N'-methylurea 181) N-5- (1 "(2-thienyl) -1-methylethyl) amino methylsulfonyl-2-methylphenylsulfonyl-N'-methylurea 182) N-5- (1- (3-thienyl) -1-methylethyl) aminocarbonyl-10-methyl-2-methylenylsulfonyl-N'-methylurea 183) N-5- (1- (2-Pyrrolyl) -1-methylethyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N'-methylurea 184) N-5- {1- (3-pyrrolyl) -1-methylethyl) aminocarbonyl- methyl-2-methylphenylsulfonyl-N'-methylurea 15 185) N-5- (1- (2-thiazolyl) -1-methylethyl) aminocarbonylmethyl-2-methylenylsulfonyl-N'-methylurea 186) N-5- ( 1- (3-Thiazolyl) -1-methylethyl) aminocarbonyl-1-methyl-2-methylthio-phenylsulfonyl-N'-methylurea 187) N-5- (1- (2-furyl) -1-methylethyl) aminocarbonyl-20 methyl 2-methylthiophenylsulfonyl-N 1 -methylthiourea 188) N-5- (1- (3-furyl) -1-methylethyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N'-methylthiourea 189) N-5- (1- ( 2-Thienyl) -1-methylethyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N1-methylthiourea 190 190) N-5- (1- (3-Thienyl) -1- methylethyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N'-methylthiourea 191} N-5- (1- (2-pyrrolyl) -1-methylethyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N1-methylthiourea 192 ) N-5- {1- (3-pyrrolyl) -1-methylethyl) aminocarbonyl-30 methyl-2-methylthiophenylsulfonyl-N'-methylthiourea 193) N-5- (1- (2-thiazolyl) -1-methylethyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N '-methylthiourea 194) N-5- (1- (3-thiazolyl) -1-methylethyl) aminocarbonyl-1-methyl-2-methylthio-phenylsulfonyl-N1-methylthiourea 35,195) N -5- (1- (2-furyl) -1-methylethyl) aminocarbonylmethyl-2-methylthio phenylsulfonyl-N'-methylurea 25 196} N-5- {1- (3-furyl) -1- methyl ethyl} aminocarbonylmethyl-2-methylthiophenylsulfonyl-N1-methylurea 197} N-5- {1- (2-thienyl) -1-methylethyl} aminocarbonylmethyl-2-methylthiophenylsulfonyl-N1-methylurea 5 198} N-5- (1- (3-Thienyl) -1-methylethyl) aminocarbonylmethyl-2-methylthiophenyl Ulfonyl-N1-methylurea 199} N-5- (1- (2-pyrrolyl) -1-methylethyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N1-methylurea 200} N-5- {1- (3-pyrrolyl) - 1-methylethyl) aminocarbonyl-10 methyl-2-methylthiophenylsulfonyl-N1-methylurea 201) N-5- {1- (2-thiazolyl) -1-methylethyl) aminocarbonylmethyl-2-methylthiophenylsulfonyl-N'-methylurea 202) N -5- (1- (2-Furyl} -1-methylethyl} aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N1-methylthiourea 15203) N-5- (1- (3-furyl) -1-methylethyl} aminocarbonylmethyl) -2-Ethoxyphenylsulfonyl-N1-methylthiourea 204) N-5- (1- (2-thienyl) -1-methylethyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N1-methylthiourea 205) N -5- (1- (3 -thienyl) -1-methylethyl) aminocarbonylmethyl-20-ethyl-2-ethoxyphenylsulfonyl-N'-methylthiourea 206) N-5- (1- (2-pyrrolyl} -1-methylethyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl -N'-methylthiourea 207) N-5- (1- (3-pyrrolyl) -1-methylethyl) aminocarbonylmethyl-2-ethoxy ifenylsulfonyl-N'-methylthiourea 25 208) N-5- (1- (2-thiazolyl) -1-methylethyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N'-methylthiourea 209) N-5- (1- (3- thiazolyl) -1-methylethyl) aminocarbonyl-1-methyl-2-ethoxyphenylsulfonyl-N'-methylthioea 210) N-5- (1- (2-furyl) -1-methylethyl} aminocarbonylmethyl-2-ethoxyphenylsulfonyl) -N1-methylurea 211) N-5- (1- (3-furyl) -1-methylethyl} aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N1-methylurea 212) N-5- (1- (2-thienyl) -1 -methylethyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N1-methylurea 35 213) N-5- (1- (3-thienyl) -1-methylethyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N1-methylurea 26 214) N- 5- (1- (2-Pyrrolyl) -1-methylethyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N'-methylurea 215) N-5- (1- (3-pyrrolyl) -1-methylethyl) aminocarbonyl -methyl-2-ethoxyphenylsulfonyl-N'-methylurea 5 216) N-5- (1- (2-thiazolyl) -1-methylethyl) aminocarbonyl ethyl 2-ethoxyphenylsulfonyl-N'-methylurea 217) N-5- (1- (2-furyl) -1-methylethyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N'-methylthiourea 218) N- 5- (1- (3-Furyl) -1-methylethyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N'-methylthiourea 219) N-5- {1- (2-thienyl) -1-methylethyl) aminocarbonylmethyl -2-propoxyphenylsulfonyl-N'-methylthiourea 220) N-5- (1- (3-thienyl) -1-methylethyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N'-methyl ourea 15 221) N-5 - (1- (2-Pyrrolyl) -1-methylethyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N'-methylthiourea 222) N-5- (1- (3-pyrrolyl) -1-methylethyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N'-methylthiourea 223) -5- (1- (2-thiazolyl) -1-methylethyl) aminocarbonyl-20-methyl-2-propoxyphenylsulfonyl-N'-methylthiourea 224) N -5- (1- (3-Thiazolyl) -1-methylethyl) aminocarbonyl-1-methyl-2-propoxyphenylsulfonyl-N'-methylthiourea 225} N-5- {1- (2-furyl) li) -1-methylethyl) aminocarbonylmethyl-2-propoxy phenylsulfonyl-N'-methylurea 25 226) N-5- (1- (3-furyl) -1-methylethyl) aminocarbonylmethyl-2-propoxy phenyl sulfonyl-N'-methylurea 227) N-5- (1- (2-thienyl) -1-methylethyl) aminocarbonylmethyl-2-propoxy phenyl sulfonyl-N'-methylurea 228) N-5- (1- ( 3-Thienyl) -1-methylethyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N'-methylurea 229) N-5- (1- (2-pyrrolyl) -1-methylethyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N 1 -methyl urea 230) N-5- (1- (3-pyrrolyl) -1-methylethyl) aminocarbonylmethyl-2-propoxyphenylsulfonyl-N'-methyl urea 35 231} n-5- (I- ( 2-Thiazolyl) -1-methylethyl) aminocarbonyl-1-methyl-2-propoxyphenylsulfonyl-N1-methylurea.

Preparation of Starting Materials Preparation of 3-sulfamoylphenylalkane carboxylic acids 4-substituted phenylalkane carboxylic acids are added with stirring and portionwise to excess chlorosulfonic acid. After stirring for 30 minutes at room temperature, the mixture is poured onto ice and the sulfonic acid chloride formed is filtered off with suction. It is dissolved in ammonia solution, stirred for 30 minutes at room temperature and the solution is neutralized with 2N hydrochloric acid. The product obtained is separated by suction filtration.

According to this method:

3-Methylphenoyl-4-methoxyphenyl-3-propionic acid m.p. 172-176 ° C

15 3-sulfamoyl-4-methoxyphenylacetic acid m.p. 164 ° C.

Preparation of 3-sulfonylamino-N- (methylaminothiocarbonyl) -4-methoxyphenylacetic acid 5 g of 3-sulfamoyl-4-methoxyphenylacetic acid Liu-20 are taken up in 3 ml of DMF and mixed with 245 mg of sodium hydroxide. minutes at 40 ° C. To it is added 328 mg of methyl isothiocyanate and stirred for an additional 2 hours at 70 ° C. To the cooled solution is added 2N hydrochloric acid and the product is filtered off with suction.

25 M.p. 174 ° C.

Preparation of N-5- (1-Phenylethyl) aminocarbonylmethyl-2-methoxysulfamoylbenzene 2.45 g (0.01 mol) of 3-sulfamoyl-4-methoxyphenylacetic acid and 4.0 g triethylamine is dissolved in 25 ml of 30 DMF and propane phosphonic acid anhydride (0.015 mol, 50% in DMF) is added followed by 1.2 g (0.01 mol) of 1-phenylethylamine under ice-cooling. Stir for 3 hours at room temperature and pour the mixture into water. After some time the product crystallizes and can be used in many cases without further purification for other reactions.

Similarly, 28 N-5- (1-phenylethyl) aminocarbonylmethyl-2-ethoxysulfamoylbenzene N-5- (1-phenylethyl) aminocarbonylmethyl-2-methylsulfamoylbenzene 5 N-5- (1-phenylbutyl) aminocarbonylmethyl is obtained. -2-etoksisul-

famoylbenzene, m.p. 156-158 ° C

N-5- (1-phenylbutyl) aminocarbonylmethyl-2-methylsulfonylbenzene, m.p. 117-118 ° C

N-5- (1-Phenylpentyl) aminocarbonylmethyl-2-methoxylisoyl-famoyl-benzene, m.p. 143-145 ° C.

General procedure for the preparation of sulfonyl (thio) ureas 1 from sulfonamides 2: A) 0.01 mol sulfonamide II is dissolved in 25 ml DMF and 0.006 mol K 2 CO 2 is added. While stirring, 0.011 mol of iso (thio) cyanate are added and the mixture is heated for about 2-6 hours at 60-80 ° C. The mixture is poured into ice water and acidified with 2N HCl. The precipitated crystals are separated by suction filtration and optionally purified by recrystallization or chromatography on silica gel. In many cases, however, the reaction is quantitative or the product crystallizes in pure form after acidification.

B) To sulfonamide 2 is added CS2 and KOH in DMF, then triphosgene to the dipotassium salt. Finally, ammonia is added and the solution acidified.

EXAMPLES Example 1 N-5- (1-Phenylethyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylthiourea

30 M.p. 175-176 ° C

Example 2 N-5- (1-Phenylethyl) aminocarbonylmethyl-2-ethoxyphenylsulfonyl-N '-methyl thiourea

Sp. 156-158 ° C 35 Example 3 29 N-5- (1-phenylethyl) aminocarbonylmethyl-2-methylphenylsulfonylphenyl-N '-methylthiourea Example 4 N-5 - ( 1-naphthylethyl (i) aminocarbonyl-1'-2-methyl-5-toxicophenylsulfonyl-N'-methylthiourea

Sp. 188-190 ° C

Example 5 N-5- {1-Phenylpropyl i) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylthiourea

10 M.p. 125-127 ° C

Example 6 N-5- (1-Phenylbutyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylthiourea

Sp. 12 - 13 ° C. Example 7 N-5- (1-phenylcyclobutylmethyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N1-methylthiourea

Sp. 195-197 ° C

Example 8 20 N-5- (1-Phenylcyclohexylmethyl) aminocarbonyl! - methyl 2-methoxyphenylsulfonyl-N * -methylthiourea

181-183 ° C

Example 9 N-5- (1- (2-Methoxyphenyl) ethyl) aminocarbonyl-2-ylmethyl-4-methoxyphenylsulfonyl-N '-methylthiourea

Sp. 178-179 ° C

Example 10 N-5- (1-Phenylpentyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N '-methylthiourea

30 M.p. 143-145 ° C

Example 11 N-5- (1-Phenylpropyl) aminocarbonylmethyl-2-methylsulfonyl-N '-methylthiourea

Sp. 117-118 ° C

35 Example 12 30 N-5- (1-Phenylbutyl) aminocarbonylmethyl-2-methylsulfonyl-4'-methylthiourea

Sp. 112-113 ° C

Example 13 5 N-5- (1-Phenylcyclobutylmethyl) aminocarbonylmethyl-2-methylphenylsulfonyl-N'-methylthiourea

Sp. 130-131 ° C

Example 14 N-5- (1-Phenylcyclohexylmethyl) aminocarbonyl-10 methyl-2-methylphenylsulfonyl-N'-methylthiourea

Sp. 145-147 ° C

Example 15 N-5- (2- (1,1R-Phenylethyl) aminocarbonyl) ethyl-2-methoxyphenylsulfonyl-N * -methylthiourea

15 M.p. 88 ° C

Example 16 N-5- (2- (1,1S-Phenylethyl) aminocarbonyl) ethyl-2-methoxyphenylsulfonyl-N'-methylthiourea

Sp. 85 ° C

Example 17 N-5- (1,1R-Phenyl-ethyl) -aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylthiourea

Sp. 150-152 ° C.

Example 18 N-5- (1,1S-Phenylethyl) aminocarbonylmethyl-2-methoxyphenylsulfonyl-N'-methylthiourea

Sp. 150-152 ° C.

Example 19 N-5- (2- (1,1S-Phenylbutyl) aminocarbonyl) ethyl-30-2-methoxyphenylsulfonyl-N * -methylthiourea

Sp. 171 ° C

Pharmacological results:

The following models can be used to determine the therapeutic properties of Compounds I: 35 (1) Duration of action potential in guinea pig nystic muscle 31 (a) Introduction ATP deficiencies observed during myocardial ischemia lead to a reduction in action potential duration. They are one of the causes of so-called reentry-5 arrhythmias, which can cause sudden cardiac death. The opening of ATP-sensitive κ channels due to ATP reduction is the cause.

(b) Method

Standard-10 standard microelectrode technology is used to measure the action potential. To this end, guinea-pigs of both sexes are struck in the head, the hearts are removed, the bony muscles are removed and hung in the living room. The organ bath is well rinsed with Ringer's solution (0.9% NaCl, 0.048% KCl, 0.024% CaCl2, 0.02% NaHCO3, and 0.1% glucose) and aerated with a gas mixture of 95 % oxygen and 5% carbon dioxide at 36 ° C. The muscle is stimulated by an electrode having a rectangular pulse of 1 V and a duration of 1 ms and a frequency of 2 Hz. The action potential is derived and recorded with an intracellular intracellular glass microelectrode filled with 3 mM KCl solution. To the test substances was added Ringer's solution at a concentration of 2.2.10 ~ 5 mol / liter. The action potential is amplified by a Hugo Sachs amplifier and visualized with an oscilloscope. The duration of action potential 25 is determined using a 95% degree of repolarization (APD95). Reductions in action potential are achieved either by the addition of a 1 μΜ solution of Hoe 234 potassium channel opener (J. Kaiser, H. Gögelein, Naunyn-Schmiedebergs Arch. Pharm. 1991, 343, R59) or by the addition of 2-deoxyglucose.

The action-reducing effect of these agents was prevented or reduced by the simultaneous administration of test substances. The test areas were added as stock solutions in the propane diol of the spa solution. The values reported are based on measurements after 30 min of addition. Glibenclamide served as a standard in these 35 measurements. The test concentration in each case is 2 x 10 ~ 6 M.

32 (c) Results:

Example # APD95 at start [ms] APD95, 30 min [ms] 5 18 179 ± 6 140 ± 20 2 173 ± 27 152 ± 6

Claims (14)

33 1. Where R (2), R (3), R (4) and Ar are as defined in claim 1 and M is an alkali-20 alkali, ammonium or tetraalkylammonium ion, reacting R {1 ) -substituted isocyanate of formula IV R (1) -NC-O IV wherein R (1) is as defined in claim 1 to 38-substituted benzenesulfonylurea Ia (E = oxygen) 1 H ) WsrYYXAr * - R {2) XR (3) or (b) Unsubstituted Benzenesulfonylurea Ia 5 [R (D = H, E-O)] is prepared by reaction of aromatic benzenesulfonamide of formula II or its salt III with trialkylsilyl isocyanate or silicon tetraisocyanate (e.g. by hydrolysis) a primary silicon-substituted benzenesulfonylurea; or 10 (c) benzenesulfonylurea 1a (E = oxygen) is prepared from aromatic benzenesulfonamide II or a salt thereof with m R (1) -substituted trichloroacetamide of formula V / HH 8 (1) 1 3 c- ^ V 0 15 em in the presence of carbon monoxide in an inert solvent; or (d) Benzenesulfonylthiourea Ib (E = S) '' VrYK '1b R (2) * R (3) is prepared from benzenesulfonamide II or a salt thereof II and R (1) substituted isothiocyanate VI 20 R (1) - N = C = S VI or 39e} The substituted benzenesulfonylthiourea of formula Ia (E = oxygen) is prepared from the benzenesulfonylthiourea of formula Ib (E = S) by a reaction reaction; or (f) benzenesulfonylurea Ia is prepared from a benzenesulfonyl halide of the formula VII e '^ VrYK * rr (2)> ^ x Y * <4> R (1) substituted urea or R (1) substituted bis (trial) -kylsilyl) with urea; or (g) benzenesulfonylurea Ia is prepared by the formula A substituted benzenesulfonylurea or thiourea compound having the formula M% // ° H, (,) rSrYrTYXAr 'Κ <2) ^ * R <s,' '((> 5) wherein R (1) is hydrogen, alkyl, having 1, 2, 3, 4, 5 or 6 C atoms or cycloalkyl having 3, 4, 5 or 6 C atoms; Compound of formula I according to claim 1, characterized in that 34 R (1) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, or cycloalkyl having 3, 4, 5 or 6 C atoms; R (2) is straight chain or branched alkyl having 1, 2, 3, 4, 5 or 6 C atoms, linear or branched to low having 1, 2, 3, 4, 5 or 6 C atoms , or cycloalkyl having 3, 4, 5 or 6 C atoms; R (3) and R (4) (the same or different) represent hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or together form a chain (0¾} 2-5; E is oxygen or sulfur; X is oxygen or sulfur; Y is a hydrocarbon chain of formula [CR (5) 2] m, R (5) is hydrogen or alkyl having 1 or 2 carbon atoms and m 15 is 1 or 2; Ar is a phenyl, thienyl, furyl, pyrrolyl, thiazolyl, naphthyl or pyridyl group which is unsubstituted or substituted with 1-3 substituents selected from alkyl having 1 or 2 C-; an atom, an alkoxy containing 1 or 2 C atoms, Cl, Br and F; and physiologically acceptable salts thereof. Compound of formula I according to claim 1, characterized in that R (1) is hydrogen or alkyl having 1 or 2 25 C atoms or cycloalkyl having 3, 4, 5 or 6 C- atoms; R (2) is a C 1-8 chain wherein 1-3 C atoms may be replaced by a heteroatom, a branched alkyl having 1, 2, 3, 4, 5 or 6 C atoms, a branched alkoxy having 1, 30 2, 3, 4, 5 or 6 C atoms, or cycloalkyl having 3, 4, 5 and 6 C atoms? R (3) and R (4) (the same or different) represent hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or together form a chain (CH 2) 2-s; 35. is broken; x is oxygen; 35 Y is a hydrocarbon radical of formula [CR (5) 2 11-2 wherein R (5) is hydrogen or alkyl having 1 or 2 carbon atoms; Ar is a phenyl, thienyl, furyl, pyrrolyl, thiazolyl, naphthyl or pyridyl group which is unsubstituted or substituted with 1 to 3 substituents selected from alkyl having 1 or 2 C atoms, alkoxy having 1 or 2 carbon atoms, Cl, Br and F; and physiologically acceptable salts thereof. Compound of formula I according to claim 1, characterized in that R (1) is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, or cycloalkyl having 3, 4, 5 or 6 C atoms; R (2) is a straight-chain or branched alkyl having 1, 2, 3, 4, 5 or 6 C atoms, a straight-chain or branched alkoxy having 1, 2, 3, 4, 5 or 6 C atoms , or cycloalkyl having 3, 4, 5 or 6 C atoms; R (3) and R (4) (the same or different) represent hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or together form a chain (CH 2) 2-s; E is sulfur; X is oxygen; Y is a hydrocarbon group of the formula [CR (5) 2] i-2 wherein R (5) is hydrogen or alkyl having 1 or 2 carbon atoms; Ar is a thienyl, furyl, pyrrolyl, thiazolyl, naphthyl or pyridyl group, in each case unsubstituted or substituted with 1-3 substituents selected from alkyl having 1 or 2 carbon atoms, alkoxy having 1 or 2 C atoms, Cl, Br and F; 30 and its physiologically acceptable salts. Compound of formula I according to claim 1, characterized in that R (1) is hydrogen or alkyl having 1 or 2 carbon atoms; R (2) ??? is a straight or branched alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms; R (3) and R (4) (same or different) represent hydrogen or alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms; E is sulfur; X is oxygen; 5. is a hydrocarbon chain of formula (CH 2) i-2; Ar is a phenyl, thienylfurylpyrrolyl, thiazolyl, naphthyl or pyridyl group which is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of alkyl having 1 or 10 2 carbon atoms , a lower one of 1 or 2 C atoms, Cl, Br and F; and physiologically acceptable salts thereof. Compound of formula I according to any one of claims 1 to 5, characterized in that R (1) is hydrogen or alkyl having 1 or 2 C atoms; R (2) is a straight or branched alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms; R (3) and R (4) (the same or different) are hydrogen or methyl; E is sulfur; X is oxygen; Y is hydrocarbons ju of the formula (CH 2) i-2; Ar is a thienyl, furyl, pyrrolyl, thiazolyl, naphthyl or pyridyl group which is unsubstituted or substituted with 1 to 3 substituents selected from alkyl having 1 or 2 carbon atoms, alkoxy having 1 or 2 C atoms, Cl, Br and F; and physiologically acceptable salts thereof. Compound of formula I according to claim 1, characterized in that R (1) is hydrogen or alkyl having 1 or 2 C atoms; R (2) is a straight or branched alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms; 37 R (3) and R (4) (same or different) are hydrogen or methyl; E is sulfur; X is oxygen; 5. is a hydrocarbon chain of formula (CH 2) i-2; Ar is phenyl unsubstituted or substituted with 1 to 3 substituents selected from alkyl having 1 or 2 C atoms, alkoxy having 1 or 2 C atoms, Cl, Br and F; 10 and its physiologically acceptable salts. A process for the preparation of a compound I according to any one of claims 1 to 7, characterized in that (a) an aromatic sulfonamide of the formula II. UV Λ YN Or ίΥϊϊΚ R (2) ^ Xh {3) R (<) Use of a compound I as claimed in claim 1, or an acceptable salt thereof, in the manufacture of a medicament for the treatment of cardiac arrhythmias. Use of compound I or a physiologically acceptable salt thereof according to claim 1 for the preparation of a medicament for the prevention of sudden cardiac death. By reaction of 10 R (1) -NH 2 amine with benzenesulfonyl isocyanate of formula VIII 0. H Or (h) Benzenesulfonylthiourea Ib is prepared by reaction of an amine of formula R (1) -NH 2 with benzenesulfonyl isothiocyanate having or (i) benzenesulfonyl or sulfinyl urea is acidified to the benzenesulfonyl urea Ia. R (2) is a C 1-6 chain wherein 1-3 C atoms may be replaced by a heteroatom O, NH or S; alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, alkoxy having 1, 2, 3, 4, 5 or 6 carbon atoms, or cycloalkyl having 3, 4, 5 or 6 carbon atoms carbon atoms; R (3) and R (4) (same or different) represent hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or together form a chain (CH 2) 2-s; E is oxygen or sulfur; X is oxygen or sulfur; 20. is a hydrocarbon chain of the formula [CR (5) 2] m if R (5) is hydrogen or alkyl having 1 or 2 carbon atoms and m is 1 or 2; Ar is a phenyl, thienyl, furyl, pyrrolyl, thiazolyl, naphthyl or pyridyl group which is unsubstituted or substituted with 1-3 substituents selected from alkyl having 1 or 2 C atoms, alkoxy having 1 or 2 carbon atoms, Cl, Br and F; and physiologically acceptable salts thereof. Use of a compound I as claimed in claim 1, or a physiologically acceptable salt thereof, in the manufacture of a medicament for the treatment of ischemic heart conditions. Use of a compound I according to claim 1, or a physiologically acceptable salt thereof, in the manufacture of a medicament for the treatment of impaired cardiac output. Use of a compound I as claimed in claim 1, or a physiologically acceptable salt thereof, in the manufacture of a medicament for improving cardiac function after cardiac transplantation. Medicament, characterized in that it contains an effective amount of a compound of formula I according to claim 1, or a physiologically acceptable salt thereof. 41